anticoagulants and anti-anemic power point Flashcards
confers biologic activity upon prothrombin and factors VII, IX, and X by participating their postribosomal modifications
vitamin K
is an essential cofactor in the carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X
vitamin K
onset of effect is delayed for 6 hours but the effect is complete by 24 hours then treating depression of prothrombin activity by excess warfarin or vitamin K deficiency
vitamin K
vitamin k has poor bioavailability following ______ administration
SQ
increases the factor VIII activity
desmopressin acetate
classic hemophilia, or hemophilia A
factor VIII deficiency
christmas disease, or hemophilia B
factor IX deficiency
concentrate contains activated clotting factors
factor IX
is a plasma protein fraction obtainable from whole blood containing fibrinogen
cryoprecipitate
Anticoagulation and fibrinolysis:
1.Degrades the clot by tissue-type or urokinase-type plasminogen activator
Endothelial cells secrete t-PA (fibrinolysis) at sites of injury, rapidly inactivated in blood
2.Thrombomodulin -blocks coagulation cascade by binding thrombin leading to inactivation of factor V and VIII
3.Release of prostacyclin-inhibits platelet aggregation and vasoconstriction
4. Antithrombin III- surface heparin-like molecules and blocks coagulation cascade
5.Tissue factor pathway inhibitor- inhibits extrinsic coagulation pathway
binds thrombin leading to inactivation of factors V and VIII…this blocks coagulation cascade
thrombomodulin
inhibits platelet degranulation, aggregation and vasoconstriction
prostacyclin
serine protease inhibitor, binds to and inactivates factors IIa, IXa, Xa, Xla, and Xlla
Antithrombin III
inhibits extrinsic coagulation pathway
tissue factor pathway inhibitor
surface heparin-like molecules (blocks coagulation cascade)
Antithrombin III
3 types of pharmacological interventions to treat thrombosis
- antiplatelet
- anticoagulant
- thrombolytic
The 4 major steps for hemostasis
- local vasoconstriction
- formation of primary hemostatic plug
- formation of thrombus (fibrin containing blood clot)
- fibrinolysis- degradation of blood clot
3 steps in primary hemostais: the platelet plug
- Vasucular injury- exposes reactive subendothelial matirix proteins
- Platelet adhesion and activation- TXA2 and integrin (IIb/IIIa)
- Platelet granule release- ADP activates integrin receptor, TXA2, calcium release
What happens during platelet adhesion and activation?
- Thromboxane A2 (TXA2) released- is a potent vasoconstrictor and platelet activator
- Conformational change in the integrin (IIb)/IIIa) receptor, restulting in fibringogen binding
What 3 molecules are released during platelet granule release?
- ADP- activates integrin receptor (IIb/IIIa)
- TXA2
- Calcium
activates integrin receptor (IIb/IIIa)
ADP
The secondary hemostasis: coagulation process involves:
Is a clotting cascade that leads to thrombin activation ad formation of fibrin fibers to stabilize hemostatic plug
Thrombin is the final active protease
The cascade is initiated via the Intrinsic and extrinsic system.
vitamin k is required to be activated throughout the intrinsic system, extrinsic system, and final common pathway.
In the final common pathway vitamin k is required to be activated for the production of prothrombin—> thrombin—>fibrinogen—->fibrin
important for clotting factors
calcium
The central role of thrombin in coaulation :
1.
2.
3.
- activates multiple clotting factors
- potent platelet activator
- activates factor XIII to cross-links the fibrin polymer (cross-linked fibrin polymer is responsible for fibrin degradation products)
prevent primary hemostastic plug formation
antiplatelet drugs
inhibit clotting cascade to ultimately prevent fibrin clot formation
anticoagulant drugs
dissolve an existing clot by digesting fibrin
thrombolytic drugs
Antiplatelet drugs: 1. 2. 3. 4. 5. 6.
- ASA
- Dipyridamole
- Clopidogrel
- Ticlopidine
- Abciximab
- Eptifibatide
selectively inhibits the synthesis of thromboxe A2 (which causes platelet aggregation and granule) by irreversible acetylation of the exzyme cyclooxygenase (COX-1)
ASA
Rapid absorption-peak (plasma) 15-20 minpost administration
ASA
Higher dose leads to inhibition of prostacyclin production and reduced efficacy of therapy
ASA
This effect persist for platelet lifespan 7-10 days
ASA
Adverse effects: increased incidence of hemorrhagic stroke; GI bleeding, tinnitus, Reye’s syndrome for young people
ASA
vasodilator that inhibits platelet function by inhibition of phosphodieserase (PDE), leads to increased intracellular cAMP levels which reduces intracellular calcium and inhibits platelet activation
Dipyridamole
Inhibits thromboxane synthase, therefore lowering the levels of TXA2 production
Dipyridamole
Short duraction of action. Primary therapeutic use is in combination with ASA to prevent cerebrovascular ischemia
Dipyridamole
Blocks P2Y12 receptor. Is a prodrug metabolized by CYP2C19, duration of the antiplatelet effect is 7-10 days
Clopidogrel
Therapuetic uses:
Reduction of the rate of stroke, MI, heart attack, unstable angina and death in patients with recent MI or stroke, peripheral arterial disease, or acute coronary syndrome. Is equivalent to ASA in the prevention of stroke
Clopidogrel
Adverse effects:
Prolonged bleeding, thrombotic thrombocytopenic purpura, FDA black box warning about CYP2C19 poor metabolizers are at high risk of treatment failure and a greater risk for major adverse CV events.
Clopidogrel
Irreversibly inhibits the P2y 12 ADP receptor.
Ticlopidine
ADP receptor blockade inhibits activation of the glycoprotein IIb/IIIa pathway. Activation of the IIb/IIIa receptor complex is the final common pathway for platelet aggregation and is important in the cross linking of platelets by fibrin
Ticlopidine
Therapuetic uses:
used as standard practice in combination with ASA (synergistically) to prevent stent thrombosis. Typically used for patients who are intolerant/allergic to ASA
Ticlopidine
Adverse effects:
Most common nausea/vomiting, diarrhea, hemorrhage.
Severe neutropenia
Rare: thrombotic thrombocytopenic purpura (TTP) (1 in 1600-4800)
Ticlopidine
Integrin receptor GPIIb/IIIa inhibitors:
1.
2.
Abciximab
Eptifibatide
Fab fragment of humanized monoclonal antibody directed against the GFPIIb receptor
Abciximab
Therapeutic uses:
when used with ASA and heparin to treat coronary thromboses or during coronary angioplasty, reduces restenosis, recurrent MI
Abciximab
Adverse effects: major hemorrhagic event 1%-10% patients, long duration of action-approx 10hours
Abciximab
Cyclic peptide inhibitor of the fibrinogen binding on the GPIIb receptor
Eptifibatide
Therapeutic uses:
acute coronary synrome and for angioplastic coronary interventions
Eptifibatide
Adverse effects:
major hemorrhage in 10% of patients
Eptifibatide
act on clotting factors present in plasma to either inhibit pro-clotting factors or activate anti-clotting factors
anticoagulants
prevent synthesis of factors via vitamin K
anticoagulants
like antiplatelet drugs, cannot dissolve a thrombus that has already formed
anticoagulants
catalyzed inhibition of cloting factors IXa, Xa and thrombin by greatly enhancing antitrombin III activity (approximatey 1000 fold) by causing conformational hange in ATIII exposing its reactive site
HMW Heparin
anticoagulant
- Testing required to determine dose effect on coagulation.
- Not absorbed by GI tract due to large molecular weight therefore use IV or SQ injection, IM injection can cause hemotomas
HMW Heparin
anticoagulant
short half life (approx 1h) means frequent injections or continuouis infusion-not suitable in outpatient setting
HMW Heparin
anticoagulant
therapeutic use:
venous thrombosis and pulmaonary embolism, angina, acute MI
HMW Heparin
anticoagulant
Does not cross the placenta: therefore is the drug of choice for anticoagulation during pregnancy
HMW Heparin
anticoagulant
contraindications:
hemorrhage (particularly intracrania) hemophilia, thrombocytopenia, hypertension, surgery of the brain, spinal cord or eye
HMW Heparin
anticoagulant
adverse effects:
hemorrhage, osteoporosis and spontaneous fractures, 1-4 % patients get HIT (systemic hypercoabulable state
HMW Heparin
anticoagulant
antagonist for HMW heparin. it combines with heparin forming a stable complex devoid of anticoaulant activity
protamine sulfate
fractionated forms of HMW heparin
Dalteparin
low molecular weight heparins
inhibit factor Xa by antithrombin, because the majority of molecules are of insufficient length to catalyze inhibition of thrombin
low molecular weight heparins
therapeutic use:
treat venous thromboembolism, thrombosis, pulmonary embolism, and unstable angina
low molecular weight heparins
neutralization of LMW heparin by protamine is
incomplete
advantages over unfractionated heparin:
longer half life (4 hours) and faster absorption time, much lower risk of thrombocytopenia and oseoporosis, once daily SQ injection administered in out pt setting, less frequent monitoring required due to more predictabl pharmacokinetic response
low molecular weight heparins
Name 4 direct thrombin inhibitors: 1. 2. 3. 4.
- hirudin
- argatroban
- bivalirudin
- dabigatran etexilate
bind to the active site of thrombin, therby inhibiting thrombin’s downstream effects
direct thrombin inhibitors
anticoagulant
specific, irreversible thrombin inhibitor used in patients with or at risk of heparin-induced thrombocytopenia
hirudin
(direct thrombin inhibitor)
(anticoagulant)
reversible thrombin inhibitor used in patients with or at risk of heparin-induced thrombocytopenia
argatroban
(direct thrombin inhibitor)
(anticoagulant)
- directly occupies the catalytic site of thrombin
* used in percutaneous coronary angioplasty
bivalirudin
(direct thrombin inhibitor)
(anticoagulant)
- Standard oral twice daily dose
- Low molecular weight pro-drug, rapidly (approx 1h) converted to active form, which binds to exosite 1 on thrombin preventing fibrinogen cleavage to insoluble fibrin
dabigatran etexilate
(direct thrombin inhibitor)
(anticoagulant)
therapeutic uses:
stroke prevention in patients with atrial fibrillation-equal efficacy to warfarin, less patient monitoring
dabigatran etexilate
(direct thrombin inhibitor)
(anticoagulant)
adverse effects:
hemorrhage, hearburn, stomach upset, increase in risk of MI
dabigatran etexilate
(direct thrombin inhibitor)
(anticoagulant)
benefits:
no patient monitoring/titration as with warfarin, rapid onset of action, no adverse drug reactions
dabigatran etexilate
(direct thrombin inhibitor)
(anticoagulant)
dicoumarol first isolated from sweet clover silage-caused hemorrhagic disease in cattle
warfarin
anticoagulant
- blocks the carboxylation of glutamate residues in prothrombin and factors VII,IX, and X
- results in biologically inactive coagulation factor molecules
warfarin
anticoagulant
the enzyme that catalyzes the carboxylation reaction, vitamin K epoxide reductase, is inhibited by therapeutic doses, preventing reductive metabolism of the inactive vitamin K epoxide to its active hydoquinone form
warfarin
anticoagulant
slow onset of action (8-12 hours)—existing clotting factors must be depleted; maximal effect 3-5 days after administration
warfarin
anticoagulant
therapeutic use:
acute DVT, pulmonary embolism, venous thromboembolism, folling acute MI, prosthetic heart valve placement, chronic atrial fib
warfarin
anticoagulant
adverse effects:
- hemorrhage, risk increases with intensity and duration of therapy
- readily crosses the placenta, can cause hemorrhage at any time and developmental defects during the 1st trimester
warfarin
anticoagulant
drug interactions:
increase effects:
ASA, anabolic sterioids, antibiotics, tamoxifen, oral hypoglycemics, vitamin K deficiency
warfarin
anticoagulant
drug interactions:
decrease effects:
* chronic alcohol abuse, oral contraceptives, corticosteroids, barbituates, increased hpatic synthesis of clotting factors, increased vitamin K intake, cholestryramine binds to this in the intestine and resuces its absorption and bioavailability
* metabolized by CYP2C9
warfarin
anticoagulant
used to reverse warfarin associated bleeding
phytonadione (vitamin K 1)
effective only if used rapidly after onset of thrombosis
thrombolytics
therapeutic uses-in hospital:
acute ischemic stroke, MI, pulmonary embolism, severe deep venous thrombosis, ascending thrombophlebitis
thrombolytics
- inhibitor of thrombolytics
* inhibits the conversion of plasminogen to plasmin
aminocaproic acid
most dangerous side effect is hemorrhage, of which intracranial hemorrhage is the most serious
thrombolytics
contraindications: brain tumor, aneurysm, hemorrhagic stroke, major surgery within the last 2 weeks, active bleeding in GI or urinary tract, severe platelet shortage or coagulation disorder, severe uncontrolled HTN
thrombolytics
hematopoiesis requires a constant supply of tree essential nutrients___________,_________,______- as well as the presence of hematopoietic growth factors
iron
vitamin B12
Folic acid
Normal values of hemoglobin in females and males:
females: 14 (+/-) 2
males: 16 (+/-) 2
normal values of hematocrit in females and males:
females: 42(+/-) 5
males: 47 (+/-) 5
normal values of reticulocytes in females and males:
1 for both
normal value for mean corpuscular hemoglobin
32-36
in the absence of adequate iron, small pale erythrocytes with insufficient hemoglobin are formed (microcytic hypochromic RBC)
iron deficiency anemia
3 oral iron medications for iron deiciency anemia:
ferrous sulfate
ferrous gluconate
ferrous fumarate
treatment with oral iron should be continued for
3-6 months to replienish iron stores
may inhibit absorption of ferrous compounds
antacids
increases the absorption of iron by approx 30%
ascorbic acid
adverse effects:
nausea, heartburn, epigastric discomfort, abdominal cramps, constipation, and diarrhea
oral iron therapy
- large amounts are toxic
* necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea, shock, letheragy, and cardiovasuclar collapse
iron toxicity
treatment of iron toxicity:
1.
2.
- whole bowel irrigation to flush out unabsorbed pills
- deferoxamin (iron chelating compound) given systemically binds absorbed oron and promotes its excretion in urine and feces
iron-deficient patients for which oral ron is not sufficient and pregnant women to create iron stores
parental iron therapy
adverse effects:
- acute hypersensitivity, including anaphylatic shock
- headache, malaise, fever, nausea and vomiting, back pain, clushing, bronchospasm, nausea and vomiting
parental iron therapy
- is a cofactor for RBC maturation
- lack of this causes abnormal DNA replication and ineffective hematopoiesis leading to megaloblastic anemia
- absorbed from gut in an intrinsic factor
vitamin b 12 deficiency
- treatment of vitamin b 12 deficiency
* limited value if patient has deficiency of intrinsic factor
oral vitamin b12 supplement
- this vitamin b 12 therapy must be maintained for life
* IM every 4 weeks is sufficient to maintain a normal concentration of vitamin b 12
cyanocobalamin
- used for IM treatment for vitamin b 12 deficiency
- now becoming more common as is more highly protein-bound and therfore remains longer in the circulation reducing regularity of injections
hydroxocobalamin
required for essential biochemical reactions that mediate synthesis of amino acids, purines, dna, and the maturation of RBCs
folic acid
- deficency results in megaloblastic anemia microscopically indistinguishable from vitamin b12 deficiency anemia
folate
causes:
- inadequate levels in diet or impaired absorpton (intestinal disease or small bowel resection)
- often seen in alcoholics with por diet, during pregnancy and lactation, patients with hemolytic anemia, cancer or renal dialysis
folic acid deficiency
drug side effects:
- methotrxate, trimethoprim and pyrimethamin, inhibit dihyrofolate reductase and may result in a deficiency
- oral contrceptives and anticonvulsants impair aborption and storage
folic acid deficiency
treatment of folic acid deficiency:
1.
2.
- folic acid oral tablets/MVI comboinations
- folinic acid (leucovorin calcium)- 5 formyl derivative of tetrahydrofolic acid-more expensive than folic acid and no greather benefit
for anemia treatment:
maintain hgb levels between
11-13
for iron therapy keep ferritin
> 100
for anemia treatment: use ____________stimulating agents or transfusions
erythropoietin
